Maintenance Of Alcohol Use Disorder Research Articles

Alcohol Use Disorder and the Gut-Brain Axis: A Narrative Review of the Role of Gut Microbiota and Implications for Treatment.

Alcohol use disorder (AUD) affects millions of people worldwide and can lead to deleterious physical and social consequences. Recent research has highlighted not only the effect of alcohol on the gut microbiome, but also the role of the gut microbiome and the gut-brain axis in the development and maintenance of alcohol use disorder. This review provides an overview of the reciprocal relationship between alcohol consumption and the gut microbiome, including the effects of alcohol on gut microbial composition, changes in gut microbial metabolites in response to alcohol consumption, and how gut microbial metabolites may modulate alcohol use behavior. We also discuss the gut-mediated mechanisms of neuroinflammation that contribute to and result from AUD, including disruption of the intestinal barrier, toll-like receptor signaling, and the activation of glial cells and immune cells. Finally, we review the current evidence on gut microbial-directed therapies for AUD and discuss the implications of this research for our understanding of the pathophysiology of AUD and future research directions.

The affective temperaments as a prognostic factor in the course of alcohol addiction – a key to enhance diagnoses and therapy?

The paper outlines the role of affective temperaments, as defined by Akiskal, in the development and maintenance of alcohol use disorders with a particular focus on the clinical course of addiction. Among affective temperaments, a cyclothymic temperament seems to play a key role in the development and maintenance of alcohol use disorders, and have the greatest influence on the clinical course of addiction. A high cyclothymic score is associated with inter alia an earlier onset of drinking and alcohol dependence, a negative course of alcohol dependence, relapse and alcohol craving. The structure of affective temperaments is also a predictor of suicidal behavior and drug addiction in the alcohol addict population. Interest has been growing regarding the role of affective temperament in the development and course of alcohol dependence; however, further research in this area is needed. An understanding of the temperamental determinants of alcohol dependence in the affective dimension may significantly support diagnostic and therapeutic procedures. Affective temperament profile may be suggestive of alcohol use disorders and may be a primary prognostic factor of craving and relapse, potential suicide, treatment motivation and the co-occurrence of drug dependence among patients with alcohol use disorder.

Mapping Dialectical Behavior Therapy Skills to Clinical Domains Implicated in Contemporary Addiction Research: A Conceptual Synthesis and Promise for Precision Medicine

Recent addiction research has identified clinical domains that are central to the development and maintenance of alcohol use disorder (AUD). Yet existing psychotherapy approaches are not typically organized around these clinical domains and are often limited in scope. Dialectical behavior therapy (DBT) is an intensive, multicomponent cognitive behavioral treatment that includes individual psychotherapy, group-based skills training, phone coaching, and consultation team for DBT therapists. Despite its efficacy on various mental health conditions, access to full DBT is often a challenge. In this paper, we describe how the skills training component of DBT can be flexibly applied to target clinical domains that underlie the three stages of the addiction cycle or impair quality of life during recovery from AUD. Using three clinical case vignettes, we illustrate how DBT skills can be mapped onto addiction clinical domains (e.g., Dialectical Abstinence and Clear Mind on executive function, STOP and TIP skills on incentive salience, Check the Facts and Opposite Action on negative emotionality, and ABC PLEASE skill on quality of life). Based on this integrated framework, we offer practical recommendations for case conceptualization, stigma reduction, and implementation through multiple delivery options. Implications on precision medicine are also discussed. Together, this conceptual synthesis serves as a bridge for practitioners to learn about contemporary addiction theories and for addiction researchers to appreciate the value of DBT in substance use treatment. The promotion of DBT skills training as a stand-alone or adjunctive intervention may help address the significant treatment gap in alcohol and substance use behaviors.

The Role of Perceived Stress in the Relation between Childhood Maltreatment and Severity of Alcohol Use Disorder: A Mediation Analysis

Introduction: Experiences of Childhood Maltreatment (CM) relate to relapse and lower treatment success in Alcohol Use Disorder (AUD), one of the most prevalent substance use disorders. However, the exact mechanisms of this relationship still remain unclear. This study examines perceived stress and “drinking to cope with negative affect” (coping) as possible mediators in this relationship. Moreover, it aims at uncovering the differential effects of the subtypes of CM. Methods: N = 96 individuals (42% women; mean age 41 ± 13 years) including healthy controls and individuals with varying severity of AUD and CM completed the Alcohol-Dependence Scale, Childhood Trauma Questionnaire, Perceived Stress Scale and German Inventory of Drinking Situations. Mediation analyses including perceived stress as a mediator between CM (and subtypes) and severity of AUD, as well as a serial mediation of the relationship between CM and AUD severity by perceived stress and coping were conducted. Results: Perceived stress significantly mediated the relation between CM and AUD severity and the serial mediation by perceived stress and coping turned out significant. Subtype-specific analyses did not yield significant results. Conclusion: This study reinforces perceived stress as a potential mechanism in the relation between CM and AUD severity. Moreover, coping further mediated the relationship between CM and AUD severity. Our results suggest including screening for CM (subtypes) in clinical routine in order to individually emphasize interventions focusing on stress regulation, as well as on developing healthy coping mechanisms, in patients with AUD. This might prevent heightened stress sensitivity, relapse and further maintenance of AUD.

Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

Dopamine D2 receptors in the bed nucleus of the stria terminalis modulate alcohol-related behaviors

Dysregulation of the dopamine (DA) system is a hallmark of substance use disorders, including alcohol use disorder (AUD). Of the DA receptor subtypes, the DA D2 receptors (D2Rs) play a key role in the reinforcing effects of alcohol. D2Rs are expressed in numerous brain regions associated with the regulation of appetitive behaviors. One such region is the bed nucleus of the stria terminalis (BNST), which has been linked to the development and maintenance of AUD. Recently, we identified alcohol withdrawal-related neuroadaptations in the periaqueductal gray/dorsal raphe to BNST DA circuit in male mice. However, the role of D2R-expressing BNST neurons in voluntary alcohol consumption is not well characterized. In this study, we used a CRISPR-Cas9-based viral approach, to selectively reduce the expression of D2Rs in BNST GABA neurons (BNSTvgat Drd2) and interrogated the impact on alcohol-related behaviors. In male mice, reduced BNSTvgat Drd2 expression potentiated the stimulatory effects of alcohol and increased voluntary consumption of 20% w/v alcohol in a two-bottle choice intermittent access paradigm. This effect was not specific to alcohol, as BNSTvgat Drd2 knockdown also increased sucrose intake in male mice. Interestingly, reduction in BNSTvgat Drd2 expression in female mice did not alter alcohol-related behaviors but lowered the threshold for mechanical pain sensitivity. Collectively, our findings suggest a role for postsynaptic BNST D2Rs in the modulation of sex-specific behavioral responses to alcohol and sucrose.

Brain proteomic atlas of alcohol use disorder in adult males

Alcohol use disorder (AUD) affects transcriptomic, epigenetic and proteomic expression in several organs, including the brain. There has not been a comprehensive analysis of altered protein abundance focusing on the multiple brain regions that undergo neuroadaptations occurring in AUD. We performed a quantitative proteomic analysis using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of human postmortem tissue from brain regions that play key roles in the development and maintenance of AUD, the amygdala (AMG), hippocampus (HIPP), hypothalamus (HYP), nucleus accumbens (NAc), prefrontal cortex (PFC) and ventral tegmental area (VTA). Brain tissues were from adult males with AUD (n = 11) and matched controls (n = 16). Across the two groups, there were >6000 proteins quantified with differential protein abundance in AUD compared to controls in each of the six brain regions. The region with the greatest number of differentially expressed proteins was the AMG, followed by the HYP. Pathways associated with differentially expressed proteins between groups (fold change > 1.5 and LIMMA p < 0.01) were analyzed by Ingenuity Pathway Analysis (IPA). In the AMG, adrenergic, opioid, oxytocin, GABA receptor and cytokine pathways were among the most enriched. In the HYP, dopaminergic signaling pathways were the most enriched. Proteins with differential abundance in AUD highlight potential therapeutic targets such as oxytocin, CSNK1D (PF-670462), GABAB receptor and opioid receptors and may lead to the identification of other potential targets. These results improve our understanding of the molecular alterations of AUD across brain regions that are associated with the development and maintenance of AUD. Proteomic data from this study is publicly available at www.lmdomics.org/AUDBrainProteomeAtlas/.

Posttraumatic stress as a moderator of the association between HPA-axis functioning and alcohol use disorder among a community sample of women currently experiencing intimate partner violence.

Women experiencing intimate partner violence (IPV) experience a heightened prevalence of alcohol use disorder (AUD). Hypothalamic-pituitary-adrenal (HPA)-axis functioning has been associated with increased risk for AUD in other populations, including individuals with posttraumatic stress disorder (PTSD) symptoms. The goal of the present study was to determine whether PTSD symptom severity exacerbates the relationship between HPA-axis functioning and AUD. Participants were 151 community women who had experienced physical or sexual IPV in the past 30 days by their current male partners and used any amount of alcohol or drugs. A two-phase emotion induction protocol was utilized: Neutral mood induction followed by randomly assigned negative, positive, or neutral emotion induction. Saliva cortisol samples were obtained immediately following the neutral mood induction (baseline HPA-axis functioning), 20 min following the individualized emotion induction script (HPA-axis reactivity), and 40 min post the emotionally evocative cue (HPA-axis recovery). Findings revealed that PTSD symptom severity moderated the relations between baseline HPA-axis functioning and HPA-axis recovery and log odds of meeting criteria for AUD. Specifically, baseline HPA-axis functioning was positively associated with log odds of meeting criteria for AUD at high (but not low) PTSD symptom severity, whereas HPA-axis recovery was negatively associated with log odds of meeting criteria for AUD at high (but not low) PTSD symptom severity. Results contribute to our understanding of the biological processes involved in the etiology and maintenance of AUD among women experiencing IPV-specifically the prominent role of PTSD symptom severity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The mediating role of alexithymia in the relationship between affective temperament and craving: Cross-sectional study conducted in a sample of bipolar and alcohol use disorder patients

BackgroundBipolar disorder (BD) and alcohol use disorder (AUD) commonly co-occur and their interplay is influenced by several factors. Alexithymia is connected to BD and AUD; affective temperaments serve as risk factors for both; craving contributes to the development and maintenance of AUD. The present study tested whether alexithymia play a mediating role in the relationship between affective temperaments and craving in alcoholic bipolar patients. Methods151 alcoholic bipolar patients (38 % females, mean age: 45.69 ± 9.04 years) were enrolled. The Mini International Neuropsychiatric Interview (MINI), the Brief Psychiatric Rating Scale (BPRS), the Toronto Alexithymia Scale (TAS-20), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego scale (TEMPS-A), and the Typology Craving Questionnaire (CTQ) were administered. Correlations among TAS-20, TEMPS-A, CTQ were conducted. Regression analyses were applied to verify the mediating hypothesis. ResultsDifficulty in identifying feelings mediated the association between anxious temperament and craving (Indirect effect: 0.42, BCaCI: 0.22–0.69), cyclothymic temperament and craving (Indirect effect: 0.55, BCaCI: 0.30–0.87), irritable temperament and craving (Indirect effect: 0.45, BCaCI: 0.19–0.80). TAS-20 difficulty in communicating feelings to others mediated the association between anxious temperament and craving (Indirect effect: 0.20, BCaCI: 0.06–0.41). LimitationsThe sample size did not allow subgroup analyses. Data were collected cross-sectionally and in a single center. We did not investigate whether BD or AUD occurred first, although it might influence the mediation role of alexithymia. ConclusionAmong alcoholic bipolar patients, assessing and targeting alexithymia may be useful to modulate craving and, in turn improve, the general mental status of patients.

The Dopamine System in Mediating Alcohol Effects in Humans.

Brain-imaging studies show that the development and maintenance of alcohol use disorder (AUD) is determined by a complex interaction of different neurotransmitter systems and multiple psychological factors. In this context, the dopaminergic reinforcement system appears to be of fundamental importance. We focus on the excitatory and depressant effects of acute versus chronic alcohol intake and its impact on dopaminergic neurotransmission. Furthermore, we describe alterations in dopaminergic neurotransmission as associated with symptoms of alcohol dependence. We specifically focus on neuroadaptations to chronic alcohol consumption and their effect on central processing of alcohol-associated and reward-related stimuli. Altered reward processing, complex conditioning processes, impaired reinforcement learning, and increased salience attribution to alcohol-associated stimuli enable alcohol cues to drive alcohol seeking and consumption. Finally, we will discuss how the neurobiological and neurochemical mechanisms of alcohol-associated alterations in reward processing and learning can interact with stress, cognition, and emotion processing.

Unraveling the epigenomic and transcriptomic interplay during alcohol-induced anxiolysis

Positive effects of alcohol drinking such as anxiolysis and euphoria appear to be a crucial factor in the initiation and maintenance of alcohol use disorder (AUD). However, the mechanisms that lead from chromatin reorganization to transcriptomic changes after acute ethanol exposure remain unknown. Here, we used Assay for Transposase-Accessible Chromatin followed by high throughput sequencing (ATAC-seq) and RNA-seq to investigate epigenomic and transcriptomic changes that underlie anxiolytic effects of acute ethanol using an animal model. Analysis of ATAC-seq data revealed an overall open or permissive chromatin state that was associated with transcriptomic changes in the amygdala after acute ethanol exposure. We identified a candidate gene, Hif3a (Hypoxia-inducible factor 3, alpha subunit), that had ‘open’ chromatin regions (ATAC-seq peaks), associated with significantly increased active epigenetic histone acetylation marks and decreased DNA methylation at these regions. The mRNA levels of Hif3a were increased by acute ethanol exposure, but decreased in the amygdala during withdrawal after chronic ethanol exposure. Knockdown of Hif3a expression in the central nucleus of amygdala attenuated acute ethanol-induced increases in Hif3a mRNA levels and blocked anxiolysis in rats. These data indicate that chromatin accessibility and transcriptomic signatures in the amygdala after acute ethanol exposure underlie anxiolysis and possibly prime the chromatin for the development of AUD.

Trait sensitivity to negative feedback determines the intensity of compulsive alcohol seeking and taking in male rats.

Background:Alcohol use disorder is one of the most common psychiatric disorders, and it is a leading cause of mortality worldwide. It has been demonstrated previously that people with alcohol use disorder are less sensitive to the negative outcomes of their actions and less able to use negative feedback to guide and adjust their ongoing behaviour. However, far less is known about the aberrant processing of negative feedback before the onset of alcohol use disorder. In this study, we investigated the theoretical claim that sensitivity to negative feedback — as a stable and enduring behavioural trait — can predict vulnerability to the development of compulsive alcohol consumption in rats.Methods:We trained and tested rats in a series of probabilistic reversal learning tests, and based on this “negative feedback sensitivity screening,” we classified each rat as more or less sensitive to negative feedback. Then, in the intermittent-access 2-bottle choice paradigm, we measured alcohol consumption in the animals classified above. In the next step, using the instrumental second-order chained schedule of alcohol reinforcement task, we examined the influence of sensitivity to negative feedback on the development of compulsive alcohol seeking behaviour. Finally, we measured how trait sensitivity to negative feedback affected the extinction and reinstatement of alcohol seeking after a period of abstinence.Results:Trait sensitivity to negative feedback predicted the vulnerability of rats to the development of compulsive alcohol seeking and consumption. We also found significant differences between the more sensitive and less sensitive groups in their propensity to extinguish alcohol seeking behaviours when the alcohol was no longer available.Limitations:The findings from our study did not answer the question of whether individual differences in sensitivity to negative feedback have a genetic basis or develop in response to postnatal experiences.Conclusion:The results of our study suggest that negative feedback sensitivity screening could be used to evaluate individual vulnerability to the development and maintenance of alcohol use disorder.

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system's involvement in the development and maintenance of alcohol use disorder (AUD). In the present study we administered the TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption on a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg. However, when 1.0 mg/kg was given on consecutive days, alcohol intake increased in the days following injections specifically in females. In a second experiment, we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the poly(I:C) dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions in alcohol intake on injection days in females that were not accompanied by subsequent increases. The poly(I:C) dose was increased to 9.0 mg/kg for one final pair of injections which led to reductions in intake in both males and females followed by a male specific delayed increase in alcohol intake. Overall, repeated poly(I:C) administration was able to increase subsequent alcohol consumption in both sexes, with females showing an increase at a lower dose than males. These findings support TLR3 agonism in contributing to increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.

Gender Differences in the Psychosocial Determinants Underlying the Onset and Maintenance of Alcohol Use Disorder.

A large number of different mechanisms have been linked to Alcohol Use Disorder (AUD), including psychosocial, neurocognitive, affective, and neurobiological factors. Gender has been shown to impact the presentation and progression of AUD; yet, little work has been done to parse the different mechanisms underlying AUD within the lens of gender differences. A review of the literature on adolescence revealed that psychosocial factors, in particular lack of family social support and interactions with peers, drive the onset of alcohol use more strongly in girls relative to boys. However, research done on gender differences in disease progression in adults remains limited. Our gender-specific analysis of the mechanisms underlying AUD in adults revealed that lack of social support was causally linked to negative affect, mental health symptoms, and AUD symptom severity in women, but not men. These novel results suggest that psychosocial factors may play a gender-specific role not only in the onset of use in adolescence, but also in the maintenance of addiction in adults. If confirmed, this suggests the need for investigating gender-specific recovery trajectories. In this perspective piece, we review the literature regarding gender differences in the onset and maintenance of AUD and present original data that support unique risk factors in women.

Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors

The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.

Alcohol-related attentional biases in recently detoxified inpatients with severe alcohol use disorder: an eye-tracking approach

BackgroundDominant theoretical models consider that attentional biases (AB) towards alcohol-related stimuli play a key role in the development and maintenance of alcohol use disorder (AUD). Their assessment has however showed high inconsistencies and has been mostly based on unreliable behavioral measures. This study evaluated the presence and extent of alcohol-related AB in recently detoxified inpatients with severe AUD by combining the visual probe task (VPT) paradigm with eye-tracking measures, known to improve the VPT reliability in subclinical populations. MethodsWe recruited 24 patients and 27 matched healthy controls. They performed the VPT (measuring reaction time when processing visual targets preceded by alcoholic and matched non-alcoholic pictures) combined with eye-tracking measures (dwell time, first fixation direction/duration, second fixation direction) during two sessions. Estimates of internal consistency, split-half reliability, and test-retest reliability were measured. ResultsPatients showed shorter dwell time for alcohol cues (p = .004, d=.853) and reduced number of fixations towards alcohol after a first fixation on non-alcohol cues (p = .012, d=.758) compared to controls. These findings suggest the presence of alcohol-related avoidance AB in detoxified patients with severe AUD. The VPT achieved excellent reliability for these eye-tracking measures. Reaction times and first fixation measures did not indicate any AB pattern and showed poor reliability. ConclusionsThe VPT, when combined with dwell time and second fixation direction, constitutes a reliable method for assessing AB in detoxified patients. It showed the presence of an alcohol-related avoidance bias in this clinical population, in contradiction with the approach bias predicted by theoretical models.

Mapping data-driven individualized neurobehavioral phenotypes in heavy alcohol drinkers.

Recent studies have examined the factor structure and associated correlates of three neurofunctional domains, executive function, incentive salience, and negative emotionality in the development and maintenance of alcohol use disorders in clinical samples. The current study sought to replicate and extend prior work by testing this 3-factor model, utilizing both exact and similar phenotypic measures, as well as novel measures, in a non-treatment-seeking sample. Self-report measures of alcohol addiction, impulsivity, behavior, and exposure to early-life stress were collected as part of baseline assessments for alcohol imaging and pharmacotherapy studies in 335 individuals. Confirmatory factor analysis (CFA) was used to examine model structure and fit. A multiple indicators, multiple causes (MIMIC) model identified predictors of latent factors identified by CFA. Results supported an intercorrelated model with three factors: executive function, incentive salience, and emotionality. All factors were associated with current AUD, and incentive salience was uniquely associated with past 30-day drinking frequency. MIMIC results identified multiple significant predictors of these latent factors, including history of alcohol use disorder, positive family history of alcohol dependence, earlier age of first drink, and a history of childhood emotional abuse and physical neglect. Our results support an intercorrelated 3-factor model of neurofunctional domains in alcohol use models, consistent with published findings. Because childhood physical neglect was a significant predictor of all latent factors, these results also highlight the significant negative impact of childhood neglect on later addiction development.

Investigating Relationships Among Distress Tolerance, PTSD Symptom Severity, and Alcohol Use

Exposure to trauma (particularly interpersonal trauma), post-traumatic stress disorder (PTSD) symptoms, and low distress tolerance (DT; the ability to tolerate negative internal states), are all related to risk for alcohol use disorders (AUD). The aim of this study was to examine the main and interactive effects of PTSD symptom severity and DT in relation to current (past 30-day) alcohol consumption and binge drinking among emerging adult men and women with a history of sexual/physical assault. Participants were 572 undergraduate students (66% women) with a history of physical/sexual assault endorsing past month alcohol use. Participants completed the Distress Tolerance Scale (DTS), the PTSD Checklist for DSM-V (PCL-5), and an abbreviated Timeline Followback Questionnaire (TLFB), which assessed past 30-day total alcohol consumption (i.e., total number of drinks) and binge drinking frequency (i.e., 5+ drinks [4+ for women]). Negative binomial regression analyses revealed that male sex, higher trauma load (i.e., total number of trauma categories endorsed), and higher PTSD symptom severity were associated with both higher number of total drinks and higher frequency of binge drinking episodes. However, DT was not associated with either alcohol outcome when PTSD symptom severity was entered in the models. The interaction of PTSD symptom severity and DT was not significantly associated with total alcohol consumption or binge drinking. These results highlight the importance of investigating the unique contributions of PTSD symptoms and DT (as well as other transdiagnostic cognitive-affective constructs) in the onset and maintenance of AUD.

Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder.

AimsThe effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABAB receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness.MethodsThis short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABAB PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABAB PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABAB PAMs to attenuate multiple alcohol-related behaviors will be discussed.ResultsPositive allosteric modulators (PAMs) of the GABAB receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABAB agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABAB PAMs for addiction treatment.ConclusionsPreclinical studies indicate that GABAB PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABAB agonism. This predicts that GABAB PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.

Subjective Responses to Alcohol in the Development and Maintenance of Alcohol Use Disorder.

Alcohol use disorder (AUD) remains an urgent public health problem. Longitudinal data are needed to clarify the role of acute subjective responses to alcohol in the development and maintenance of excessive drinking and AUD. The authors report on 10 years of repeated examination of acute alcohol responses in the Chicago Social Drinking Project. Young adult drinkers (N=190) participated in an initial alcohol challenge (0.8 g/kg of alcohol compared with placebo) that was repeated 5 and 10 years later. They were also assessed on drinking behavior and AUD symptoms at numerous intervals across the decade. Retention was high, as 184 of the 185 (99%) nondeceased active participants completed the 10-year follow-up, and 91% (163 of 179) of those eligible for alcohol consumption engaged in repeated laboratory testing during this interval. At the end of the decade, 21% of participants met criteria for past-year AUD. Individuals who reported the greatest alcohol stimulation, liking, and wanting at the initial alcohol challenge were most likely to have developed AUD 10 years later. Further, alcohol-induced stimulation and wanting increased in reexamination testing among those with the highest AUD symptoms as the decade progressed. Initial stimulant and rewarding effects of alcohol predicted heavy alcohol use, and the magnitude of these positive subjective effects increased over a 10-year period in those who developed AUD compared with those who did not develop the disorder. The findings demonstrate systematic changes in subjective responses to alcohol over time, providing an empirical basis for prevention, early intervention, and treatment strategies.